We identified loss-of-function mutations in the gene encoding the secreted growth factor progranulin (PGRN) as a major cause of familial frontotemporal lobar degeneration with ubiquitin and TDP-43-positive inclusions (FTLD-U). The exact role of PGRN in neurons has yet to be established, however, the loss of functional PGRN in FTLD-U implicates its essential function in neuronal survival. The identification of TDP-43 as the pathological protein, not only in patients with FTLD-U with mutations in PGRN, but also in the majority of patients with ALS and in 20-30% of pathologically confirmed Alzheimer's disease (AD) patients further suggests a role for the TDP-43 protein in a unifying neurodegenerative disease mechanism underlying these disorders. The recent identification of mutations in TDP-43 as a direct cause of neurodegeneration in sporadic and familial patients with ALS strongly supports this notion. Our working hypothesis is that the PGRN/TDP-43 axis plays a role in multiple neurodegenerative diseases including AD. In this project we will use both genetic and proteomic methods to help understand the role of PGRN and TDP-43 in AD and other neurodegenerative disorders. The Specific Aims of this project are: 1. To determine the role of genetic variants in PGRN and TARDBP (TDP-43) in the development and presentation of AD. We will perform genetic association studies of PGRN and TARDBP in Caucasian and African/American AD case-control populations and study the effect of common genetic variability on PGRN and TDP-43 expression levels, TDP-43 pathology and disease. 2. To identify novel PGRN and TDP-43 interacting proteins using somatic brain transgenic technology. We will use somatic brain transgenic technology to express dual affinity tagged PGRN and TDP-43 proteins in the mouse brain to identify binding partners of both PGRN and TDP-43. Proteins will be identified by proteomic technologies. Subsequent studies will validate whether PGRN/TDP-43 proteins interact in human brain tissue and are altered by disease state. The proposed studies are relevant to fully appreciate the contribution of genetic variants in PGRN and TARDBP to the development and presentation of AD. Identifying the protein networks of PGRN and TDP-43 will be critical for understanding the pathways of neurodegeneration mediated by PGRN and TDP- 43 and may lead to the identification of novel therapeutic targets.